Weight gain during olanzapine/fluoxetine combination (OFC) therapy is very common. We examined early (at 2 weeks) weight gain as a predictor of later (at 26 weeks) substantial weight gain in patients with treatment-resistant depression during OFC pharmacotherapy. Data were analyzed from 2 studies (Study 1 and Study 2)-each with an acute, double-blind phase and an open-label phase-in patients who completed 26 weeks of open-label treatment (N = 306). Mean patient age was 46 years; the majority was female and white. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were examined using early weight gain of 2 kg or more as a predictor of 10 kg or more substantial weight gain. Sensitivity (true positive rate) and specificity for Study 1 (n = 73) were 33% and 71%, respectively; PPV and NPV were 23% and 80%, respectively. Sensitivity and specificity for Study 2 (n = 233) were 52% and 70%, respectively; PPV and NPV were 31% and 85%, respectively. Overall, in the 2 trials analyzed, for patients who did not gain 2 kg or more (2.54 lb) in the first 2 weeks of OFC treatment, the observed frequency was 16.3% for gaining 10 kg or more at 26 weeks. Compared to those with early weight gain, patients without early weight gain were less likely to have substantial weight gain after OFC treatment. Additional research is needed to further explore the predictive power of early weight gain for subsequent substantial weight gain in patients with treatment-resistant depression treated with OFC.